Genetics of inflammatory bowel diseases

The inflammatory bowel diseases (IBD), Crohn disease and ulcerative colitis, are immune-mediated disorders resulting in chronic, relapsing inflammation of the gastrointestinal tract. The complex nature of IBD supports the notion that its origin is likely multifactorial, constituting both genes and environmental factors. It has been hypothesized that environmental factors and maladaptive immune responses to gastrointestinal flora generate a dysregulated inflammatory cascade creating mucosal injury in genetically susceptible individuals. Over the last decade, considerable interest and research has focused on the genetic aspect of IBD. The identification of linkage between Crohn disease and the pericentromeric region of chromosome 16 (IBD1) by Hugot in 1996 spawned a series of genome scans and linkage analyses in search of susceptibility and phenotypic modifier genes (Nature 379:821–3, 1996). In 2001, the discovery that specific polymorphisms in the CARD15/NOD2 gene at the IBD1 locus were associated with Crohn disease engendered a new era of genotype–phenotype investigations (Nature 411:599–603, 2001; Nature 411:603–6, 2001). The advent of genome-wide association studies has resulted in the successful identification of new, well-replicated disease associations. The heterogeneity of IBD phenotypes suggests that it is a polygenic disorder in which susceptibility loci act in epistasis with other disease-modifying genes and the environment to produce disease. Understanding genetic associations of IBD can provide patients and their families with useful information that may help them cope with the disease. Furthermore, as our knowledge of genotype–phenotype associations grows, it is anticipated that genotyping at the onset of disease may enable physicians to predict disease course and tailor medical therapies specific for each patient.